Development Of Metal Complexes Research Articles

Mitochondria-targeting metallodrugs for cancer therapy: perspectives from cell death modes.

Mitochondria, recognized as the cellular powerhouses, are indispensable organelles responsible for crucial cellular processes, such as energy metabolism, material synthesis, and signaling transduction. Their intricate involvement in a broad spectrum of diseases, particularly cancer, has propelled the exploration of mitochondria-targeting treatment as a promising strategy for cancer therapy. Since the groundbreaking discovery of cisplatin, the trajectory of research on the development of metal complexes have been marked by continuous advancement, giving rise to a diverse array of metallodrugs characterized by variations in ligand types, metal center properties, and oxidation states. By specifically targeting mitochondria, these metallodrugs exhibit the remarkable ability to elicit various programmed cell death pathways, encompassing apoptosis, autophagy, and ferroptosis. This review primarily focuses on recent developments in transition metal-based mitochondria-targeting agents, offering a comprehensive exploration of their capacity to induce distinct cell death modes. The aim is not only to disseminate knowledge but also to stimulate an active field of research toward new clinical applications and novel anticancer mechanisms.

Photoexcitation of Distinct Divalent Palladium Complexes in Cross‐Coupling Amination Under Air

AbstractThe development of metal complexes that function as both photocatalyst and cross‐coupling catalyst remains a challenging research topic. So far, progress has been shown in palladium(0) excited‐state transition metal catalysis for the construction of carbon‐carbon bonds where the oxidative addition of alkyl/aryl halides to zero‐valent palladium (Pd0) is achievable at room temperature. In contrast, the analogous process with divalent palladium (PdII) is uphill and endothermic. For the first time, we report that divalent palladium can act as a light‐absorbing species that undergoes double excitation to realize carbon‐nitrogen (C−N) cross‐couplings under air. Differently substituted aryl halides can be applied in the mild, and selective cross‐coupling amination using palladium acetate as both photocatalyst and cross‐coupling catalyst at room temperature. Density functional theory studies supported by mechanistic investigations provide insight into the reaction mechanism.

Photoexcitation of Distinct Divalent Palladium Complexes in Cross-Coupling Amination Under Air.

The development of metal complexes that function as both photocatalyst and cross-coupling catalyst remains a challenging research topic. So far, progress has been shown in palladium(0) excited-state transition metal catalysis for the construction of carbon-carbon bonds where the oxidative addition of alkyl/aryl halides to zero-valent palladium (Pd0 ) is achievable at room temperature. In contrast, the analogous process with divalent palladium (PdII ) is uphill and endothermic. For the first time, we report that divalent palladium can act as a light-absorbing species that undergoes double excitation to realize carbon-nitrogen (C-N) cross-couplings under air. Differently substituted aryl halides can be applied in the mild, and selective cross-coupling amination using palladium acetate as both photocatalyst and cross-coupling catalyst at room temperature. Density functional theory studies supported by mechanistic investigations provide insight into the reaction mechanism.

Synthetic applications of biologically important Mannich bases: An updated review

Mannich bases are the beta-amino ketones carrying compounds. Mannich reaction is a nucleophilic addition reaction (nucleophiles such as halogen ions (I-, Br-, Cl- ), the hydroxide ion (OH- ), cyanide ion (CN-), ammonia and water, which involves the condensation of three components, viz., ammonia or a primary amine or a secondary amine or with amides, a non-enolizable aldehyde, usually formaldehyde and a compound containing an active hydrogen atom. These three compounds condense with the concomitant release of the water molecule to produce a new base known as a mannich base, in which the active hydrogen is replaced by an amino methyl group. During the past decades, there has been a great deal of interest in the synthesis of mannich bases. Mannich base can be synthesized by using microwave irradiation, one pot, catalyst-free, retrospective asymmetric synthesis, solvent-free and ultrasonic-assisted synthetic techniques. The literature studies enlighten the fact that mannich bases are a key step in the synthesis of a wide variety of natural products, pharmaceuticals and so forth. Mannich bases play a vital role in the coordination chemistry and the development of metal complexes. Mannich bases have remained an important and popular area of research due to their simple synthesis, adaptability and diverse range of applications. Thus, mannich bases and their derivatives may be further used for enormous biological applications with potent effects.

Auto-programmed construction of an iron-incorporated cobalt-molybdenum complex towards enhanced electrocatalytic water oxidation

Development of metal complexes which can be used directly as electrocatalysts for oxygen evolution reaction (OER) is arousing great interest although still in its infancy. Here, an amorphous iron-incorporated cobalt-molybdenum-dithiooxamide (Dto) complex, Fe-CoMo(Dto), which can be applied directly for water oxidation, has been developed using an one-step room-temperature coordination polymerization and self-assembly process. In-situ electrochemical activation of Fe-CoMo(Dto) during electrocatalytic operation promotes structural evolution to form electrocatalytically active species for OER. Detailed investigation of the intermediates obtained after different cyclic voltammetry (CV) cycles of OER measurement showed that amorphous spherical Fe-CoMo(Dto) nanoparticles evolve gradually into corresponding metal (oxyhydr)oxides with hexagonal nanoplate shapes, which have been identified to be real active species for enhanced OER activity. Consequently, the so-activated Fe-CoMo(Dto) complex exhibits remarkable electrocatalytic activity for OER, with a low overpotential of 294 mV at a current density of 10 mA cm−2 and a reduced Tafel slope of 66 mV dec−1.

Rising Interest in the Development of Metal Complexes in Cancer Immunotherapy.

Metal complexes have shown great potential in cancer immunotherapy. This review briefly introduces the basic concepts and strategies of cancer immunotherapy and summarizes the recent discoveries on the immune effects of traditional platinum-based anticancer compounds. In addition, we also outline the latest research progresses on metal complexes for cancer immunotherapy focusing on platinum, ruthenium, iridium, rhenium and copper complexes. Finally, the research perspectives and unsolved problems on the applications of metallo-anticancer agents in cancer immunotherapy are purposed.

Development of Metal Complexes to Utilize Visible-Light Energy into Molecular Transformation

Development of Metal Complexes to Utilize Visible-Light Energy into Molecular Transformation

Klinische Entwicklung von Metallkomplexen als Photosensibilisatoren für die photodynamische Therapie von Krebs

AbstractKrebs hat sich in den letzten Jahrzehnten zu einer der häufigsten krankheitsbedingten Todesursachen der Welt entwickelt. Neben den am häufigsten angewendeten Techniken (Chirurgie, Immuntherapie, Strahlentherapie oder Chemotherapie) wird der photodynamischen Therapie zunehmend Aufmerksamkeit gewidmet. Die überwiegende Mehrheit der klinisch eingesetzten Photosensibilisatoren ist jedoch nicht ideal und weist mehrere Einschränkungen auf, darunter schlechte Wasserlöslichkeit, schlechte Photostabilität und langsame Ausscheidung aus dem Körper, was zu Photosensibilität führt. In dem Bemühen, diese Nachteile zu überwinden, wird der Einbindung eines Metallions viel Aufmerksamkeit gewidmet. In diesem Kurzaufsatz wird die klinische Entwicklung von metallhaltigen Verbindungen wie Purlytin®, Lutrin®/Antrin®, Photosens®, TOOKAD® soluble oder TLD‐1433 kritisch diskutiert.

MN4-based G4-Ligands as Potential Antitumor Agents: A Review

Cisplatin-based metal drugs have been widely used clinically as anticancer agents. However, these drugs also harm ordinary tissues because cisplatin kills cancer cells by attacking genomic DNA. Therefore, it has been shown that cisplatin-based metal drugs have some serious side effects that cannot be avoided. In order to replace the target site of genomic DNA, G-quadruplex nucleic acid is considered to be an alternative and attractive target for anticancer agents because G-quadruplex always folds into a parallel topology and is, therefore, more important than DNA. This review discussed the recent advancements in the rational design and the development of metal complexes containing anticancer drugs to interact and stabilize or cleave the G4 structure selectively. Further, we also highlighted the G4-interacting transition metal complexes, interacting modes, and their potentials to serve as anticancer drugs in the medical field. The significance of this survey lies in designing the metallodrugs from the most fundamental characteristic of electronic structural engineering to an increasingly reasonable dimension of bio-science.

Ruthenium complexes with asymmetric hydroxy- and methoxy-substituted bipyridine ligands

The development of metal complexes with ligands capable of proton transfer can result in significant advances in Proton Coupled Electron Transfer (PCET) chemistry, specifically understanding how these reactions occur mechanistically in the excited state. The synthesis of three ruthenium complexes containing asymmetric bipyridine ligands: [Ru(bpy)2(4bpyOH)]2+, [Ru(bpy)2(4bpyOMe)]2+, and [Ru(bpy)2(44′bpy(OH)(OMe))]2+ (bpy = 2,2′-bipyridine; 4bpyOH = 4-hydroxy-2,2′-bipyridine; 4bpyOMe = 4-methoxy-2,2′-bipyridine; 44′bpy(OH)(OMe) = 4-hydroxy-4′-methoxy-2,2′-bipyridine) are reported. These complexes were studied using both experimental and computational methods. These studies indicate that the methoxy-substitution gives similar electron-donating properties to the hydroxy-substitution, meaning that the methoxy-substitution is a good control when examining electron transfer in the absence of proton transfer. Potential versus pH diagrams show that [Ru(bpy)2(4bpyOH)]2+ has a RuIII/II reduction potential of 0.97 V vs. Ag/AgCl in aqueous acidic solution that decreases to 0.76 V vs. Ag/AgCl when deprotonated. The [Ru(bpy)2(44′bpy(OH)(OMe))]2+, with an additional methoxy-substituent, has a RuIII/II reduction potential that is slightly lower with a potential of 0.92 V vs. Ag/AgCl in acidic aqueous solution that decreases to 0.74 V vs. Ag/AgCl when deprotonated. These complexes are comparable to other hydroxy- and methoxy-substituted polypyridyl ruthenium complexes reported previously, showing the additive effects of hydroxy- and methoxy-substitutions on the reduction potential of the RuIII/II wave and spectroscopic shifts that occur as the ligand scaffold is altered.

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.

Recent progress in the development of metal complexes as β-amyloid imaging probes in the brain.

In this review, we have focused on the recent progress in metal complexes that are able to bind to β-amyloid (Aβ) species. We have discussed various radioactive complexes of 99mTc, 68Ga, 64Cu, 89Zr, and 111In, which were designed as Aβ imaging agents for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, non-radioactive Re and Ru complexes as Aβ sensors using luminescence methods, and Gd3+ complexes as contrast agents for magnetic resonance imaging (MRI).

Reprint of: Structural, electronic and acid/base properties of [Ru(bpy)(bpy(OH)2)2]2+ (bpy = 2,2′-bipyridine, bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine)

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy=2,2′-bipyridine, bpy(OH)2=4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504cm−1 red shift from λmax=468nm to λmax=593nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

Structural, electronic and acid/base properties of [Ru(bpy)(bpy(OH)2)2]2+ (bpy = 2,2′-bipyridine, bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine)

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy=2,2′-bipyridine, bpy(OH)2=4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504cm−1 red shift from λmax=468nm to λmax=593nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

The Combined Therapeutical Effect of Metal-based Drugs and Radiation Therapy: The Present Status of Research

Conventional chemotherapy and radiation treatment are two cornerstones of cancer treatment but efforts are required to improve their "therapeutic window". The development of metal complexes, including platinum, has had an enormous impact on current cancer chemotherapy. However, these chemotherapeutic drugs can be employed only in the management of a limited number of cancers and, furthermore, their use causes significant side effects. Research over the past 10 years has produced new complexes containing heavy atoms other than platinum, such as iron, cobalt, or gold, which have been used in phase I and phase II trials. Recent preclinical research has shown promising results also using titanium, ruthenium, copper and silver. The anticancer activity of metal-based compounds and nanoparticles (gold and gadolinium in particular) is presently under evaluation in several laboratories in combination with or without X-ray therapy. In fact, if present in sufficiently high concentrations in the tumors, metals can act as a radiotherapy adjuvant: they possess an increased capability to absorb the X-ray radiation with respect to the water-based tissues. Low energy electrons will be then released close to the metal and, therefore, determine a local dose enhancement. This review will focus on the anticancer properties of new drugs and on the rationale for testing their usefulness in combined treatment.

Binding of zinc(II) macrocycles toward carboxylate ligands

Three new zinc(II) complexes, Zn(L1)(NO3)2(1), {[Zn(L1)(fumarate)]·2H2O}n(2) and {[Zn(L2)(fumarate)]·DMF}n(3) (L = 3,14-dimethyl-2,6,13,17-tetraazatricyclo [14,4,01.18,07.12]docosane) have been synthesized and characterized by analytical, spectroscopic, thermal and X-ray diffraction methods. The structure of the discrete neutral complex (1) shows that the central zinc(II) ion is coordinated axially by two nitrate ligands. In the structures (2) and (3), the carboxylate groups of the bridging fumarate ligands are coordinated to zinc(II) macrocycles, resulting in the formation of 1D coordination polymers. Apart from the fairly strong Zn–O bonds in (2) and (3), it is observed that the hydrogen bonds between the pre-organized N–H groups of the macrocycle and axial ligands appear to be important for the design and development of metal complexes having a strong Zn–O bond.

Metal Complexes, their Cellular Targets and Potential for Cancer Therapy

The development of metal complexes with anticancer activity has had an enormous impact on cancer chemotherapy. The discovery of cisplatin in the 1960's represented a landmark achievement and ushered in a new era in cancer treatment. Despite the fact that cisplatin has achieved significant clinical benefit for several types of solid tumors, its effectiveness has been hampered by toxic side effects and tumor resistance that often leads to the occurrence of secondary malignancies. However, discovery and use of cisplatin have encouraged investigators to search for and develop novel non platinum-containing metal species with superior anti-cancer activity and low side effects. As examples, gallium salts and gold complexes have been evaluated in phase I and phase II trials. Copper-chelating compounds have also shown promising results in both preclinical and clinical studies. This review provides a comprehensive overview of various non platinum metal complexes and metal-chelating compounds and discusses their potential molecular targets in tumor cells and their applications in cancer therapy.

Non Platinum Metal Complexes as Anti‐cancer Drugs

The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. However, the spectrum of cancers that can be treated with platinum agents is narrow and treatment efficacy suffers from side effects and resistance phenomena. These unresolved problems in platinum-based anti-cancer therapy have stimulated increased research efforts in the search for novel non platinum-containing metal species as cytostatic agents. Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible. Thus, complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or gallium central atoms have already been evaluated in phase I and phase II trials. This review covers some relevant examples of preclinical and clinical research on novel non platinum metal complexes.